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Microcephaly associated with congenital heart defect: Barbu et al
Journal Club
www. AJOG.org
Microcephaly associated with congenital heart defect: Barbu et al Isabelle Wilkins, MD; George A. Macones, MD, MSCE, Associate Editor The article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Barbu D, Mert I, Kruger M, Bahado-Singh RO. Evidence of fetal central nervous system injury in isolated congenital heart defect: microcephaly at birth. Am J Obstet Gynecol 2009;201:43.e1-7. The full discussion appears at www.AJOG.org, pages e7-12.
DISCUSSION QUESTIONS
What was the study question?
What was the study design?
How were cases and controls identified? Do the conclusions correspond with earlier work? Why are these findings biologically plausible? What challenges accompany a prospective study design? What might be the best antenatal testing in this population? How will these findings shape patient counseling and care?
From the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL: Moderator Isabelle Wilkins, MD Professor and Director Discussants Maria Colon, MD Fellow Meredith Cruz, MD Fourth-year resident Roa Qato, MD Third-year resident Jennifer Damlich Fourth-year medical student 0002-9378/free © 2009 Published by Mosby, Inc. doi: 10.1016/j.ajog.2009.05.018
See related article, page 43
118
C
ongenital heart defects (CHDs) are relatively common, occurring in about 1% of live births, according to the American Heart Association. Obstetricians are generally aware of who may be at risk, and we know how to screen patients with prenatal imaging studies. Those of us who perform or interpret those studies may know a bit more about classification of lesions, but few accepted guidelines exist for antenatal management, and once these babies are delivered, neonatologists and pediatric cardiologists take over. Prenatal consultations with these services are usually confined to discussions of how to follow the fetus for prenatal heart failure or worsening of cardiac status and planning for delivery; for example, determining whether a specialized center is essential and how immediate neonatal resuscitation will proceed. Most obstetricians know little about the long-term outcome of babies who have had a CHD diagnosed before birth. Aside from cardiac disorders, these patients have a higher than expected incidence of neurodevelopmental delay. While this may be related to a variety of neonatal and childhood incidents, including intraoperative events during corrective cardiac surgery, a growing body of medical literature points to possible in utero origins for this damage.
A U SEFUL S IGN So how do we study whether or not a fetus was neurologically damaged in utero? Barbu and colleagues, the authors of the article discussed in this month’s meeting of the Journal Club, used neonatal microcephaly as a marker for in utero compromise. In this retrospective
American Journal of Obstetrics & Gynecology JULY 2009
hospital-based study, the researchers looked at all babies with a diagnosis of CHD who had been born at Children’s Hospital of Michigan. They retrieved information about birthweight and head circumference, looked for associated anomalies, such as syndromes or chromosomal abnormalities, and eliminated cases with other potential explanations for developmental delay or small head circumference. Finally, they went back to the maternal records for demographic information to eliminate confounders. The authors found that the mean head circumference was significantly smaller in neonates with CHDs compared with controls. Because the absolute amount of the difference was small, they also looked at the rate of microcephaly and found that it was more common than it was among control infants. Their definition of microcephaly was a head circumference below the 3rd percentile, and they adjusted for gestational age. One would expect approximately 3% of their controls to have microcephaly. In fact, the rate was quite a bit higher at 8%. If this is a chance finding, their abnormal results would be more significant. However, it does raise the question of whether their population has other factors that might interfere with the generalizability of the findings. Overall, it appears that significantly more neonates with CHD had microcephaly when compared with controls. This very worrisome and important finding is similar to what other groups have discovered. Once the authors analyzed these results by type of CHD, they learned that the associations were true for some CHDs and not others. For example, hypoplastic left heart was linked
Journal Club
www.AJOG.org with microcephaly but aortic stenosis was not.
S MALL B ABIES ; B IG Q UESTIONS After data from neonates who were small for gestational age (SGA) were removed from the calculations related to specific defects, only the association between coarctation/aortic arch hypoplasia and microcephaly remained significant, and it was slightly less significant than it had been when all neonates were considered together. The researchers attributed the loss of significance in the relationships between microcephaly and tetralogy of Fallot and hypoplastic left ventricle with the resulting small sample size. This is important, since the definition of microcephaly is less clear in infants with intrauterine growth retardation (IUGR). However, it is possible that IUGR, in itself, is a risk factor for poor outcome; that it might contribute disproportionately to a poor prognosis. For example, might it be possible that the lost association between microcephaly and specific CHDs was not a result of small sample size but to a lower prevalence of microcephaly among neonates who had a CHD but were of normal size? Perhaps the group of neonates who were SGA should be studied separately, as well. At this time, the best in utero evaluation and management of a fetus with IUGR and an associated congenital anomaly has yet to be determined.
C HALLENGES A HEAD When investigating the limitations of a retrospective study, it is always tempting to ask for a prospective trial to follow up the findings. The study by Barbu et al raises many important questions including whether compromised fetuses can be identified before delivery, what form the compromise takes, whether the process
can be monitored and/or interrupted, and whether aggressive intervention in the natural history of these disorders improves outcome. In studying the association between microcephaly and CHDs, there are some obvious limitations to a prospective approach. First, we would likely not ascertain all cases of CHD, as many go undetected prenatally. Furthermore, it is also difficult to make a prospective diagnosis of IUGR and microcephaly. Presumably, the only way to prevent ongoing damage is to identify a fetus at risk and intervene to correct the problem. The authors suggest that once a diagnosis of a CHD and microcephaly are made, follow-up might include nonstress testing, biophysical profiles, and Doppler studies of blood flow to the head. Yet, it is not clear that testing would determine which fetuses would ultimately have a neurologic insult or which would be at risk of an insult that has yet to occur. At present, correcting inadequate oxygenation is only possible through early delivery, but prematurity also has a clear association with developmental delay. In short, we are far from being able to make clinical recommendations based on findings from this study. Another issue of concern is the likelihood of false-positive results with antenatal testing. Though the suggested tests seem like reasonable, noninvasive, monitoring tools, all forms of antenatal testing have a false-positive rate. Again, the results could lead to iatrogenic prematurity, and this could add to the burden of the infant’s physical condition, since premature babies with cyanotic CHD have a poorer prognosis than those who have been delivered at term. Our difficulty, therefore, does not lie in the way Barbu and colleagues performed the study, but rather in what we,
as clinicians, should do with the information it provides. This study advances our knowledge of the natural history of these disorders but offers no firm guidance on how the data should be applied to our patients. The authors correctly state that their tentative recommendations for antenatal testing and consideration of early delivery are, at the moment, without adequate support. Journal Club members wholeheartedly agreed with this point and were extremely concerned about the potential downside of these recommendations. Nonetheless, this necessary work furthers our understanding of these disorders, their progression in utero, and how they adversely affect the fetus. Generally, the group found the work to be a welcome advance. However, we felt the findings could not be used to formulate recommendation for obstetric management. Our Journal Club panel was not convinced that early delivery would lead to better outcomes, and therefore, we agreed that it was not indicated in these babies. This article explores a new and essential field. The fetus is often cared for in a stepwise fashion by specialists, whereas the best approach to understanding and tending to these patients is to offer a continuum of care from a team of providers who bring their own viewpoints to the table. Still, even when a team of experts is in place, its members often do not have the detailed information about the natural history of a given fetal disorder, and this makes it difficult to determine the best therapeutic plan. The work by Barbu and colleagues emphasizes that this is indeed the case with CHDs, but it also gives us a better insight into the chalf lenges ahead.
JULY 2009 American Journal of Obstetrics & Gynecology
119
www. AJOG.org
Microcephaly associated with congenital heart defect: Barbu et al Isabelle Wilkins, MD; George A. Macones, MD, MSCE, Associate Editor The article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Barbu D, Mert I, Kruger M, Bahado-Singh RO. Evidence of fetal central nervous system injury in isolated congenital heart defect: microcephaly at birth. Am J Obstet Gynecol 2009;201:43.e1-7. The full discussion appears at www.AJOG.org, pages e7-12.
DISCUSSION QUESTIONS
What was the study question?
What was the study design?
How were cases and controls identified? Do the conclusions correspond with earlier work? Why are these findings biologically plausible? What challenges accompany a prospective study design? What might be the best antenatal testing in this population? How will these findings shape patient counseling and care?
From the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL: Moderator Isabelle Wilkins, MD Professor and Director Discussants Maria Colon, MD Fellow Meredith Cruz, MD Fourth-year resident Roa Qato, MD Third-year resident Jennifer Damlich Fourth-year medical student 0002-9378/free © 2009 Published by Mosby, Inc. doi: 10.1016/j.ajog.2009.05.018
See related article, page 43
118
C
ongenital heart defects (CHDs) are relatively common, occurring in about 1% of live births, according to the American Heart Association. Obstetricians are generally aware of who may be at risk, and we know how to screen patients with prenatal imaging studies. Those of us who perform or interpret those studies may know a bit more about classification of lesions, but few accepted guidelines exist for antenatal management, and once these babies are delivered, neonatologists and pediatric cardiologists take over. Prenatal consultations with these services are usually confined to discussions of how to follow the fetus for prenatal heart failure or worsening of cardiac status and planning for delivery; for example, determining whether a specialized center is essential and how immediate neonatal resuscitation will proceed. Most obstetricians know little about the long-term outcome of babies who have had a CHD diagnosed before birth. Aside from cardiac disorders, these patients have a higher than expected incidence of neurodevelopmental delay. While this may be related to a variety of neonatal and childhood incidents, including intraoperative events during corrective cardiac surgery, a growing body of medical literature points to possible in utero origins for this damage.
A U SEFUL S IGN So how do we study whether or not a fetus was neurologically damaged in utero? Barbu and colleagues, the authors of the article discussed in this month’s meeting of the Journal Club, used neonatal microcephaly as a marker for in utero compromise. In this retrospective
American Journal of Obstetrics & Gynecology JULY 2009
hospital-based study, the researchers looked at all babies with a diagnosis of CHD who had been born at Children’s Hospital of Michigan. They retrieved information about birthweight and head circumference, looked for associated anomalies, such as syndromes or chromosomal abnormalities, and eliminated cases with other potential explanations for developmental delay or small head circumference. Finally, they went back to the maternal records for demographic information to eliminate confounders. The authors found that the mean head circumference was significantly smaller in neonates with CHDs compared with controls. Because the absolute amount of the difference was small, they also looked at the rate of microcephaly and found that it was more common than it was among control infants. Their definition of microcephaly was a head circumference below the 3rd percentile, and they adjusted for gestational age. One would expect approximately 3% of their controls to have microcephaly. In fact, the rate was quite a bit higher at 8%. If this is a chance finding, their abnormal results would be more significant. However, it does raise the question of whether their population has other factors that might interfere with the generalizability of the findings. Overall, it appears that significantly more neonates with CHD had microcephaly when compared with controls. This very worrisome and important finding is similar to what other groups have discovered. Once the authors analyzed these results by type of CHD, they learned that the associations were true for some CHDs and not others. For example, hypoplastic left heart was linked
Journal Club
www.AJOG.org with microcephaly but aortic stenosis was not.
S MALL B ABIES ; B IG Q UESTIONS After data from neonates who were small for gestational age (SGA) were removed from the calculations related to specific defects, only the association between coarctation/aortic arch hypoplasia and microcephaly remained significant, and it was slightly less significant than it had been when all neonates were considered together. The researchers attributed the loss of significance in the relationships between microcephaly and tetralogy of Fallot and hypoplastic left ventricle with the resulting small sample size. This is important, since the definition of microcephaly is less clear in infants with intrauterine growth retardation (IUGR). However, it is possible that IUGR, in itself, is a risk factor for poor outcome; that it might contribute disproportionately to a poor prognosis. For example, might it be possible that the lost association between microcephaly and specific CHDs was not a result of small sample size but to a lower prevalence of microcephaly among neonates who had a CHD but were of normal size? Perhaps the group of neonates who were SGA should be studied separately, as well. At this time, the best in utero evaluation and management of a fetus with IUGR and an associated congenital anomaly has yet to be determined.
C HALLENGES A HEAD When investigating the limitations of a retrospective study, it is always tempting to ask for a prospective trial to follow up the findings. The study by Barbu et al raises many important questions including whether compromised fetuses can be identified before delivery, what form the compromise takes, whether the process
can be monitored and/or interrupted, and whether aggressive intervention in the natural history of these disorders improves outcome. In studying the association between microcephaly and CHDs, there are some obvious limitations to a prospective approach. First, we would likely not ascertain all cases of CHD, as many go undetected prenatally. Furthermore, it is also difficult to make a prospective diagnosis of IUGR and microcephaly. Presumably, the only way to prevent ongoing damage is to identify a fetus at risk and intervene to correct the problem. The authors suggest that once a diagnosis of a CHD and microcephaly are made, follow-up might include nonstress testing, biophysical profiles, and Doppler studies of blood flow to the head. Yet, it is not clear that testing would determine which fetuses would ultimately have a neurologic insult or which would be at risk of an insult that has yet to occur. At present, correcting inadequate oxygenation is only possible through early delivery, but prematurity also has a clear association with developmental delay. In short, we are far from being able to make clinical recommendations based on findings from this study. Another issue of concern is the likelihood of false-positive results with antenatal testing. Though the suggested tests seem like reasonable, noninvasive, monitoring tools, all forms of antenatal testing have a false-positive rate. Again, the results could lead to iatrogenic prematurity, and this could add to the burden of the infant’s physical condition, since premature babies with cyanotic CHD have a poorer prognosis than those who have been delivered at term. Our difficulty, therefore, does not lie in the way Barbu and colleagues performed the study, but rather in what we,
as clinicians, should do with the information it provides. This study advances our knowledge of the natural history of these disorders but offers no firm guidance on how the data should be applied to our patients. The authors correctly state that their tentative recommendations for antenatal testing and consideration of early delivery are, at the moment, without adequate support. Journal Club members wholeheartedly agreed with this point and were extremely concerned about the potential downside of these recommendations. Nonetheless, this necessary work furthers our understanding of these disorders, their progression in utero, and how they adversely affect the fetus. Generally, the group found the work to be a welcome advance. However, we felt the findings could not be used to formulate recommendation for obstetric management. Our Journal Club panel was not convinced that early delivery would lead to better outcomes, and therefore, we agreed that it was not indicated in these babies. This article explores a new and essential field. The fetus is often cared for in a stepwise fashion by specialists, whereas the best approach to understanding and tending to these patients is to offer a continuum of care from a team of providers who bring their own viewpoints to the table. Still, even when a team of experts is in place, its members often do not have the detailed information about the natural history of a given fetal disorder, and this makes it difficult to determine the best therapeutic plan. The work by Barbu and colleagues emphasizes that this is indeed the case with CHDs, but it also gives us a better insight into the chalf lenges ahead.
JULY 2009 American Journal of Obstetrics & Gynecology
119